Stable pharmaceutical composition of buprenorphine and preparation method and use thereof

Abstract

Provided is a pharmaceutical composition including buprenorphine, a derivative thereof, or a pharmaceutically acceptable salt thereof, a stabilizer, a biocompatible solvent, and at least one compound represented by Formula (IIA), (IIB) or (IIC), wherein R1 is hydrogen, a C1-C20 alkylcarbonyl group, or a C6-C18 arylcarbonyl group, and wherein the compound of Formula (IIA), (IIB) and (IIC) each have an amount of less than 1% w/w based on the total weight of the pharmaceutical composition during a shelf life of the pharmaceutical composition. Also provided is a method for preparing the pharmaceutical composition and a method for treating opioid addiction, pain, and/or depression in a subject in need thereof by administering the pharmaceutical composition to the subject.

1 - 20 . (canceled) 
     
     
         21 . A pharmaceutical composition having a shelf life of at least twenty months, comprising:
 at least one active pharmaceutical ingredient chosen from buprenorphine, a derivative thereof, or a pharmaceutically acceptable salt thereof;   at least one stabilizer effective to stabilize the at least one active pharmaceutical ingredient during the shelf life;   at least one biocompatible solvent effective to form a mixture in the pharmaceutical composition of the at least one active ingredient and the at least one stabilizer; and   at least one compound of formulae (IIA), (IIB), or (IIC):   
       
         
           
           
               
               
           
         
         
           wherein in formulae (IIA), (IIB), and (IIC), R 1  is independently chosen from hydrogen, C 1 -C 20  alkylcarbonyl groups, or C 6 -C 18  arylcarbonyl groups; and 
         
         wherein the compounds of formulae (IIA), (IIB), and (IIC) are independently present in amounts less than 1% w/w, based on the total weight of the pharmaceutical composition, during the shelf life of the pharmaceutical composition. 
       
     
     
         22 . The pharmaceutical composition according to  claim 21 , wherein the compounds of formula (IIA), (IIB), and (IIC) are independently present in amounts less than 0.5% w/w, based on the total weight of the pharmaceutical composition, during the shelf life of the pharmaceutical composition. 
     
     
         23 . The pharmaceutical composition according to  claim 21 , wherein the shelf life is at least twenty months at ambient temperature or a temperature below ambient temperature. 
     
     
         24 . The pharmaceutical composition according to  claim 21 , wherein the at least one active pharmaceutical ingredient is chosen from compounds of formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is chosen from hydrogen, C 1 -C 20  alkylcarbonyl groups, or C 6 -C 18  arylcarbonyl groups. 
       
     
     
         25 . The pharmaceutical composition according to  claim 21 , wherein the at least one active pharmaceutical ingredient is present in an amount ranging from 5% w/w to 80% w/w, based on the total weight of the pharmaceutical composition. 
     
     
         26 . The pharmaceutical composition according to  claim 21 , wherein the at least one stabilizer is present in an amount ranging from 0.01% w/w to 10% w/w, based on the total weight of the pharmaceutical composition. 
     
     
         27 . The pharmaceutical composition according to  claim 21 , wherein the at least one stabilizer is chosen from vitamin E, a derivative of vitamin E, ascorbic acid, butylated hydroxyanisole, and combinations of two or more thereof. 
     
     
         28 . The pharmaceutical composition according to  claim 27 , wherein the vitamin E or derivative of vitamin E are chosen from α-tocopherol, β-tocopherol, γ-tocopherol, 5-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, 5-tocotrienol, D-α-tocopherol polyethylene glycol 1000 succinate, and combinations of two or more thereof. 
     
     
         29 . The pharmaceutical composition according to  claim 21 , wherein the at least one biocompatible solvent is chosen from N-methyl-2-pyrrolidone, polyethylene glycol 400, polyethylene glycol 4000, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N,N-dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol, and combinations of two or more thereof. 
     
     
         30 . The pharmaceutical composition according to  claim 21 , wherein the composition has a color score of less than Gardner 4. 
     
     
         31 . A method of preparing the pharmaceutical composition according to  claim 21 , the method comprising adding at least one active pharmaceutical ingredient and at least one stabilizer in at least one biocompatible solvent to form the pharmaceutical composition, wherein the at least one active pharmaceutical ingredient is chosen from buprenorphine, a derivative thereof, and a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method according to  claim 31 , further comprising stirring the pharmaceutical composition to form a homogeneous solution. 
     
     
         33 . The method according to  claim 32 , wherein the stirring is performed with heating. 
     
     
         34 . The method according to  claim 32 , further comprising filtering the homogeneous solution to obtain a filtered homogeneous solution. 
     
     
         35 . The method according to  claim 32 , further comprising sterilizing the homogeneous solution to obtain a sterilized pharmaceutical composition. 
     
     
         36 . The method according to  claim 35 , wherein the sterilizing is chosen from thermal sterilization, filtration sterilization, irradiation sterilization, and combinations or two or more thereof. 
     
     
         37 . The method according to  claim 31 , wherein the compounds of formulae (IIA), (IIB), and (IIC) are formed by degradation of the at least one active pharmaceutical ingredient. 
     
     
         38 . A method for treating opioid addiction, pain, and/or depression in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of the pharmaceutical composition according to  claim 21 . 
     
     
         39 . The method according to  claim 38 , wherein the pharmaceutical composition is administered to the human subject three times per day, two times per day, once per day, once every two days, once every three days, once every four days, once every five days, once every six days, once per week, two times per week, three times per week, four times per week, five times per week, six times per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every ten weeks, once every twelve weeks, once every four months, once every five months, or once every six months. 
     
     
         40 . The method according to  claim 38 , wherein the pharmaceutical composition is administered to the human subject via subcutaneous administration, intravenous administration, intramuscular administration, intradermal administration, transdermal administration, sublingual administration, topical administration, intraperitoneal administration, intraarticular administration, transmucosal administration, intraorgan administration, intraosseous administration, or oral administration.